Cameron Jessie M, Levandovskiy Valeriy, Mackay Neviana, Raiman Julian, Renaud Deborah L, Clarke Joe T R, Feigenbaum Annette, Elpeleg Orly, Robinson Brian H
Metabolism Research Programme, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Am J Med Genet A. 2006 Jul 15;140(14):1542-52. doi: 10.1002/ajmg.a.31313.
We have diagnosed dihydrolipoamide dehydrogenase (DLD) deficiency in two male second cousins, who presented with markedly different clinical phenotypes. Patient 1 had a recurrent encephalopathy, and patient 2 had microcephaly and lactic acidosis. Their presentation is unusual, in that the DLD subunit deficiency had little effect on pyruvate dehydrogenase complex activity, but caused a severe reduction in the activities of other enzymes that utilize this subunit. We have identified two mutations in the DLD gene in each patient. The second cousins have one novel mutation in common resulting in a substitution of isoleucine for threonine (I47T), which has not been previously reported in the literature. Patient 1 has a second mutation that has been reported to be common in the Ashkenazi Jewish population, G229C. Patient 2 has a second mutation, E375K, which has also been previously reported in the literature. Enzyme kinetic measurements on patient fibroblasts show that under certain conditions, one heteroallelic mutation may have a higher K(m). This may account for the differing clinical phenotypes. These findings have important repercussions for other patients with similar clinical phenotypes, as DLD activity is not normally measured in cases with normal PDHc activity.
我们在两名男性二级表亲中诊断出二氢硫辛酰胺脱氢酶（DLD）缺乏症，他们表现出明显不同的临床表型。患者1患有复发性脑病，患者2患有小头畸形和乳酸性酸中毒。他们的表现不同寻常，因为DLD亚基缺乏对丙酮酸脱氢酶复合体活性影响不大，但导致利用该亚基的其他酶的活性严重降低。我们在每位患者的DLD基因中鉴定出两个突变。这两名二级表亲有一个共同的新突变，导致异亮氨酸替代苏氨酸（I47T），此前文献中未见报道。患者1有另一个在阿什肯纳兹犹太人群中常见的突变，G229C。患者2有另一个突变，E375K，此前文献中也有报道。对患者成纤维细胞的酶动力学测量表明，在某些条件下，一个杂合等位基因突变可能具有更高的米氏常数（K(m)）。这可能解释了不同的临床表型。这些发现对其他具有相似临床表型的患者具有重要影响，因为在丙酮酸脱氢酶复合体（PDHc）活性正常的病例中通常不检测DLD活性。
